Immunological memory is characterized by the ability to respond specifically and more rapidly upon a subsequent encounter with a pathogen or antigen. This rapid and specific memory response upon recall is the basis for vaccination. Understanding the mechanisms that regulate immune memory is critical for the rational design of vaccines. We have recently discovered that the intracellular molecule mTOR is a major regulator of memory CD8 T cell differentiation. In vivo administration of rapamycin, a specific inhibitor of mTOR, into mice infected with LCMV significantly enhanced both the quantity and the quality of the virus-specific memory CD8 T cell response. More importantly, we have shown that mTOR acts intrinsically in antigen-specific CD8 T cells to regulate memory differentiation. In this proposal we will investigate the following: 1) role of mTOR-dependent translational control in memory CD8 T cell differentiation; 2) determine if autophagy regulates memory CD8 T cell differentiation; 3) and investigate if we can harness the mTOR pathway to enhance memory CD8 T cell responses and anti-viral immunity after preventative and therapeutic vaccination. The experiments proposed in this grant should yield new insights into the mechanisms of memory differentiation and provide a framework for the rational design of vaccines that elicit long-term CD8 T cell protective immunity. ) PUBLIC HEALTH RELEVANCE: Memory CD8 T cells are an essential component of protective immunity, and generating effective memory CD8 T cell populations with large quantity and superior quality is a major goal of successful vaccines against chronic viral infections. We have found that mTORC1 regulates memory CD8 T cell development but the molecular mechanism remains unresolved. Uncovering the mechanism will not only give us a better understanding of memory T cell development but also for establishing a new and more specific molecular target for vaccine development.)